ABSTRACT
A series of novel highly active androgen receptor (AR) antagonists containing spiro-4-(5-oxo-3-phenyl-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile core was designed based on the SAR studies available from the reported AR antagonists and in silico modeling. Within the series, compound (R)-6 (ONC1-13B) and its related analogues, including its active N-dealkylated metabolite, were found to be the most potent molecules with the target activity (IC50, androgen-sensitive human PCa LNCaP cells) in the range of 59-80 nM (inhibition of PSA production). The disclosed hits were at least two times more active than bicalutamide, nilutamide and enzalutamide within the performed assay. Several compounds were classified as partial agonists. Hit-compounds demonstrated benefit pharmacokinetic profiles in rats. Comparative SAR and 3D molecular docking studies were performed for the hit compounds elucidating the observed differences in the binding potency.
Subject(s)
Androgen Receptor Antagonists/chemical synthesis , Androgen Receptor Antagonists/pharmacology , Drug Design , Imidazolidines/chemical synthesis , Imidazolidines/pharmacology , Receptors, Androgen/metabolism , Androgen Receptor Antagonists/metabolism , Androgen Receptor Antagonists/pharmacokinetics , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Chemistry Techniques, Synthetic , Humans , Imidazolidines/metabolism , Imidazolidines/pharmacokinetics , Male , Molecular Docking Simulation , Protein Conformation , Rats , Rats, Sprague-Dawley , Receptors, Androgen/chemistryABSTRACT
A series of next in class small-molecule hepatitis C virus (HCV) NS5A inhibitors with picomolar potency containing 2-pyrrolidin-2-yl-5-{4-[4-(2-pyrrolidin-2-yl-1H-imidazol-5-yl)buta-1,3-diynyl]phenyl}-1H-imidazole cores was designed based on the SAR studies available for the reported NS5A inhibitors. Compound 13a (AV4025), with (S,S,S,S)-stereochemistry (EC50 = 3.4 ± 0.2 pM, HCV replicon genotype 1b), was dramatically more active than were the compounds with two (S)- and two (R)-chiral centers. Human serum did not significantly reduce the antiviral activity (<4-fold). Relatively favorable pharmacokinetic features and good oral bioavailability were observed during animal studies. Compound 13a was well tolerated in rodents (in mice, LD50 = 2326 mg/kg or higher), providing a relatively high therapeutic index. During safety, pharmacology and subchronic toxicity studies in rats and dogs, it was not associated with any significant pathological or clinical findings. This compound is currently being evaluated in phase I/II clinical trials for the treatment of HCV infection.
Subject(s)
Antiviral Agents/pharmacology , Drug Discovery , Hepacivirus/drug effects , Imidazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Animals , Antiviral Agents/metabolism , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Chlorocebus aethiops , Clinical Trials as Topic , Dogs , Female , Humans , Imidazoles/metabolism , Imidazoles/pharmacokinetics , Imidazoles/toxicity , Male , Mice , Molecular Docking Simulation , Protein Conformation , Rats , Vero Cells , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolismABSTRACT
Recently new drugs targeting androgen-dependent axis have been approved for the treatment of castration-resistant prostate cancer (CRPC) - Zytiga and Xtandi (formerly MDV3100), several other candidates (for example, ARN-509) are in early phases of clinical trials. However despite significant improvement in overall survival with new treatments it is evident that resistance to these drugs develops. One of the approaches to overcome it is combination therapy and from this point of view some potential for drug-drug interactions can limit the application of the drug. We describe here the preclinical development of ONC1-13B, antagonist of androgen receptor, with similar to MDV3100 and ARN-509 mechanism of action. It efficiently inhibits DHT-stimulated PSA expression and proliferation of prostate cancer cells, prevents binding of androgens to the AR ligand-binding domain, androgen-stimulated AR nuclear translocation and coactivator complex formation. In the LnCaP-Z2 xenograft model of prostate cancer ONC1-13B inhibits tumor growth and suppresses PSA expression. The in vivo activity of ONC1-13B is comparable to that of MDV3100 at similar doses, and even higher, calculated per unit of concentration in plasma. Distribution of ONC1-13B to the brain is less than that shown for MDV3100 and ARN-509, decreasing the risk of GABA-related seizure development. Additionally ONC1-13B induces significantly lower in vitro CYP3A activity than for example MDV3100 (known strong CYP3A inducer) or ARN-509 and could be well suited for co-therapy with drugs that are known CYP3A substrates. Thus ONC1-13B is a new promising antiandrogen demonstrating high efficacy in a preclinical model of prostate cancer, with lower potential for seizures and drug-drug interaction.
